Progesterone receptor (PR) and the ErbB family of receptor tyrosine kinases are major factors in breast cancer. In its classical mechanism of action, PR acts as a ligand-induced transcription factor. Upon progestin binding, PR translocates to the nucleus and binds to specific progesterone response elements (PREs) in the promoter of target genes (27). In addition to its direct transcriptional effects, PR activates signal transduction pathways in breast cancer cells through a rapid or nongenomic mechanism (5,19).
On the other hand, the ErbBs family of membrane receptor tyrosine kinases is composed of four members: epidermal growth factor receptor (EGFR/ErbB-1), ErbB-2, ErbB-3, and ErbB-4. ErbBs ligands include all isoforms of heregulins (HRG), which bind to ErbB-3 and ErbB-4 and recognize EGF-R and ErbB-2 as co-receptors, and the epidermal growth factor (EGF) which binds to EGF-R (28). Upon ligand binding, ErbBs dimerize and their intrinsic tyrosine kinase activity is stimulated, which leads to the activation of signal transduction pathways that mediate ErbBs proliferative effects. Although ErbB-2 is an orphan receptor, it participates in an extensive network of ligand-induced formation of ErbBs dimers. ErbB-2 has been shown to migrate to the nuclear compartment where it binds DNA at specific sequences, HER-2 associated sequences (HAS) (30). Through this function as a transcription factor, ErbB-2 modulates the expression of the cyclooxigenase-2 (COX-2) gene (30). Association of ErbB-2 with the COX-2 promoter was detected in breast cancer cell lines overexpressing ErbB-2, as well as in ErbB-2-positive human primary breast tumors (30). Overexpression of ErbB-2 is associated with increased metastatic potential, poor prognosis, and therapeutic resistance in mammary tumors.
The present invention addresses previous shortcomings in the art by providing methods of treating cancer and methods of inhibiting cancer cell proliferation, particularly methods of treating breast cancer.